Translational Research Network Research Articles

Kif20a inhibition reduces migration and invasion of pancreatic cancer cells

BackroundThe Translational Genome Research Network in Pancreatic Cancer performed a meta-analysis of publicly available various high-throughput gene analysis panels to identify drugable targets. There, the most differentially expressed gene between normal and cancerous pancreas was Kif20a. The aim of the study was to verify this expression pattern and further characterize Kif20a in pancreatic cancer. Materials and methodsDetailed expression analyses were carried out in pancreatic tissues and in a wide panel of pancreatic cells including ductal adenocarcinoma (PDAC) and neuroendocrine-cancer cell lines as well as immortalized human pancreatic ductal epithelial and primary stellate cells using quantitative real-time polymerase chain reaction, immunohistochemistry, immunofluorescence, and immunoblot analyses. Effects on proliferation, apoptosis, and cell cycle were assessed by MTT assays, caspase-cleavage assays, and fluorescence-activated cell sorting analysis after Kif20a silencing. Cell motility was assessed by migration and invasion assays as well as time-lapse microscopy. ResultsMean Kif20a messenger RNA expression was 18.4-fold upregulated in PDAC tissues compared with that in the normal pancreas. In line, neuroendocrine-cancer cell lines display a 1.6-fold increase and ductal adenocarcinoma cell lines a 11-fold increase of Kif20a messenger RNA (P = 0.009) in comparison with primary stellate cells. A 7.3-fold overexpression was also found in immortalized pancreatic ductal epithelial cells. Kif20a silencing with small interfering RNA molecules resulted in an inhibition of proliferation, motility, and invasion of pancreatic cancer cell lines. ConclusionsTargeting Kif20a reduces proliferation, migration, and invasion of pancreatic cancer cells. Together with its significant overexpression in PDAC, this makes it a potential target for diagnostic and interventional purposes.

Safety of stromal vascular fraction cells applications in chronic pain

Autologous stromal vascular fraction (SVF) can be enzymatically released from lipoaspirate obtained under local anesthesia. SVF is known to have regenerative, anti-inflammatory, pain mitigating, and immune-modulatory properties. Our translational research network has been studying the safety and efficacy of SVF since 2012. Almost 100 related physician teams around the world are applying the same institutional review board–approved methods of SVF production, which use a surgically closed SVF isolation system. During the same outpatient surgical procedure, procured SVF is administered according to strict investigative protocols to mitigate diseases associated with chronic pain including arthritis, autoimmune disease, neurodegenerative disease, and various inflammatory conditions. The shared research collaborative online database contains safety and efficacy data on more than 3500 patients. Our processed SVF contains valuable anti-inflammatory cytokine growth factors in addition to both adult mesenchymal and hematopoietic stem cells targeting damaged, or inflamed tissue. SVF administration may potentially play a large role in the outpatient treatment of pain. In this article, we describe our protocol for the production and administration of SVF, and its safety and efficacy in the treatment of pain associated with chronic conditions.

Newborn DNA Storage Raises Serious Privacy Concerns

Newborn DNA Storage Raises Serious Privacy Concerns

Patterns of collaboration in complex networks: the example of a translational research network

BackgroundThis paper examines collaboration in a complex translational cancer research network (TRN) made up of a range of hospital-based clinicians and university-based researchers. We examine the phenomenon of close-knit and often introspective clusters of people (silos) and test the extent that factors associated with this clustering (geography, profession and past experience) influence patterns of current and future collaboration on TRN projects. Understanding more of these patterns, especially the gaps or barriers between members, will help network leaders to manage subgroups and promote connectivity crucial to efficient network function.MethodsAn on-line, whole network survey was used to collect attribute and relationship data from all members of the new TRN based in New South Wales, Australia in early 2012. The 68 members were drawn from six separate hospital and university campuses. Social network analysis with UCInet tested the effects of geographic proximity, profession, past research experience, strength of ties and previous collaborations on past, present and future intended partnering.ResultsGeographic proximity and past working relationships both had significant effects on the choice of current collaboration partners. Future intended collaborations included a significant number of weak ties and ties based on other members’ reputations implying that the TRN has provided new opportunities for partnership. Professional grouping, a significant barrier discussed in the translational research literature, influenced past collaborations but not current or future collaborations, possibly through the mediation of network brokers.ConclusionsSince geographic proximity is important in the choice of collaborators a dispersed network such as this could consider enhancing cross site interactions by improving virtual communication technology and use, increasing social interactions apart from project related work, and maximising opportunities to meet members from other sites. Key network players have an important brokerage role facilitating linkages between groups.

Parental permission for pilot newborn screening research: guidelines from the NBSTRN.

There is broad recognition of the need for population-based research to assess the safety and efficacy of newborn screening (NBS) for conditions that are not on current panels. However, prospective population-based research poses significant ethical, regulatory, and logistical challenges. In the context of NBS, there have been a variety of approaches that address parental decision-making in pilot studies of new screening tests or conditions. This article presents an ethical and legal analysis of the role of parental permission by the Bioethics and Legal Work Group of the Newborn Screening Translational Research Network created under a contract from the National Institute of Child Health and Human Development to the American College of Medical Genetics and Genomics. Circumstances are outlined in which a waiver of documentation of permission or a waiver of permission may be ethically and legally appropriate in the NBS context. These guidelines do not constitute American Academy of Pediatrics policy.

Leadership in complex networks: the importance of network position and strategic action in a translational cancer research network

BackgroundLeadership behaviour in complex networks is under-researched, and little has been written concerning leadership of translational research networks (TRNs) that take discoveries made ‘at the bench’ and translate them into practices used ‘at the bedside.’ Understanding leaders’ opportunities and behaviours within TRNs working to solve this key problem in implementing evidence into clinical practice is therefore important. This study explored the network position of governing body members and perceptions of their role in a new TRN in Sydney, Australia. The paper asks three questions: Firstly, do the formal, mandated leaders of this TRN hold key positions of centrality or brokerage in the informal social network of collaborative ties? Secondly, if so, do they recognise the leadership opportunities that their network positions afford them? Thirdly, what activities associated with these key roles do they believe will maximise the TRN’s success?MethodsSemi-structured interviews of all 14 governing body members conducted in early 2012 explored perceptions of their roles and sought comments on a list of activities drawn from review of successful transdisciplinary collaboratives combined with central and brokerage roles. An on-line, whole network survey of all 68 TRN members sought to understand and map existing collaborative connections. Leaders’ positions in the network were assessed using UCInet, and graphs were generated in NetDraw.ResultsSocial network analysis identified that governing body members had high centrality and high brokerage potential in the informal network of work-related ties. Interviews showed perceived challenges including ‘silos’ and the mismatch between academic and clinical goals of research. Governing body members recognised their central positions, which would facilitate the leadership roles of leading, making decisions, and providing expert advice necessary for the co-ordination of effort and relevant input across domains. Brokerage potential was recognised in their clearly understood role of representing a specialty, campus or research group on the governing body to provide strategic linkages. Facilitation, mentoring and resolving conflicts within more localised project teams were spoken of as something ‘we do all the time anyway,’ as well as something they would do if called upon. These leadership roles are all linked with successful collaborative endeavours in other fields.ConclusionsThis paper links the empirical findings of the social network analysis with the qualitative findings of the interviews to show that the leaders’ perceptions of their roles accord with both the potential inherent in their network positions as well as actual activities known to increase the success of transdisciplinary teams. Understanding this is key to successful TRNs.

Who are the key players in a new translational research network?

BackgroundProfessional networks are used increasingly in health care to bring together members from different sites and professions to work collaboratively. Key players within these networks are known to affect network function through their central or brokerage position and are therefore of interest to those who seek to optimise network efficiency. However, their identity may not be apparent. This study using social network analysis to ask: (1) Who are the key players of a new translational research network (TRN)? (2) Do they have characteristics in common? (3) Are they recognisable as powerful, influential or well connected individuals?MethodsTRN members were asked to complete an on-line, whole network survey which collected demographic information expected to be associated with key player roles, and social network questions about collaboration in current TRN projects. Three questions asked who they perceived as powerful, influential and well connected. Indegree and betweenness centrality values were used to determine key player status in the actual and perceived networks and tested for association with demographic and descriptive variables using chi square analyses.ResultsResponse rate for the online survey was 76.4% (52/68). The TRN director and manager were identified as key players along with six other members. Only two of nine variables were associated with actual key player status; none with perceived. The main finding was the mismatch between actual and perceived brokers. Members correctly identified two of the three central actors (the two mandated key roles director and manager) but there were only three correctly identified actual brokers among the 19 perceived brokers. Possible reasons for the mismatch include overlapping structures and weak knowledge of members.ConclusionsThe importance of correctly identifying these key players is discussed in terms of network interventions to improve efficiency.

Federal committee supports adding Pompe disease to screening panel

Federal committee supports adding Pompe disease to screening panel

Standards of care in neuromuscular fields

There is general consensus that consensus guidelines for care standards are an important tool to provide both healthcare professionals and the patient community with up to date information about all aspects of best practices in a specific disease area. The specific development of care guidelines for neuromuscular diseases poses a number of challenges. All neuromuscular diseases are rare and many show a broad spectrum of clinical and genetic heterogeneity. A paucity of randomized controlled trials for most conditions means that best-practice care guidelines are often non-existent or poorly developed. Where they exist, healthcare professionals may be unaware of them. In many cases the lack of care guidelines contributes to a lack of clinical trial activity, as the implementation of care guidelines is also a prerequisite for a reliable comparison of outcome measures in clinical trials, especially in the neuromuscular disease field, where trials are normally multi-centric and international. Over the past years there have been various collaborative efforts to achieve trial readiness for a number of neuromuscular diseases by establishing care guidelines, patient registries and networks of care and trial sites. For some of the most common neuromuscular diseases like spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD) there are now international care guidelines for healthcare professionals and patients and families. Key factors that have helped to establish these care guidelines were the involvement of patient organizations, translational research networks, and health agencies and combining existing evidence with consensus among a large number of experts in different care areas. Once care guidelines have been established, it is important to disseminate them to the stakeholder community through clinics, meetings, journal and website publications, media interviews, patient registries and professional training courses. It is also crucial to keep care guidelines updated and to take new therapeutic developments and health research outcomes into account. Once care guidelines have been agreed and disseminated, it then becomes important to monitor their implementation and to assess whether they do indeed have a positive impact on health. This is particularly important for guidelines that are based on expert opinions that lack higher levels of evidence. Finally, we need to better understand why, despite agreed upon care guidelines for various neuromuscular diseases, many patients do not receive the treatment they describe.

More states screen for severe combined immunodeficiency

More states screen for severe combined immunodeficiency

How reference networks develop, implement, and monitor guidelines

Rare diseases pose many challenges. A paucity of randomised controlled trials for most conditions means that best-practice care guidelines are often non-existent or poorly developed. Where they exist, healthcare professionals may be unaware of them. Furthermore, evaluation of guidelines is difficult, as traditional methods of health-care research (such as hospital admissions and mortality statistics with ICD codes) are not applicable to rare diseases. The CARE-NMD project to improve care for Duchenne muscular dystrophy (DMD) provides an example of how Reference Networks may develop, implement and monitor rare disease guidelines. The development of the DMD care guidelines was facilitated by the US Centres for Disease Control, and led by patient organisations, translational research networks, and health agencies. In the absence of overwhelming clinical trial evidence, 84 international experts used the RAND/UCLA Appropriateness Method (RAM) to generate consensus on the necessity and appropriateness of clinical interventions and assessments. Yet despite the guidelines, many DMD patients do not receive the treatment they describe. CARE-NMD has established a Reference Network of care centres for DMD in Europe, to disseminate guidelines, evaluate current practice and identify reasons for non-compliance, and assess guideline impact on quality of life. Dissemination, via professional and patient networks, has addressed the problem of a lack of awareness of guidelines for this rare disease. Strategies have included presentations at meetings, journal and website publications, media interviews, and professional training courses tailored to local needs in East European partner countries. The ‘Family Guide’, a more accessible version of the care guidelines, is now available in over 20 languages and has been very well received. To monitor implementation, the project has conducted the largest ever cross-sectional study of DMD patients and their families (n=1677, response rate 66%) across 7 European countries. This assessed – via process and outcome indicators – whether the care they receive aligns with the consensus guidelines, and reported quality of life. In addition, a survey of healthcare professionals has been distributed to care sites in these countries via the Care and Trial Site Registry (CTSR), an online self-registration platform for neuromuscular centres developed by the TREAT-NMD network of excellence. This now includes information on patient cohort, care settings, research activities and clinical trial capabilities of more than 200 sites. A Reference Network such as CARE-NMD enables implementation, assessment and monitoring of care guidelines for rare diseases. The data it gathers will be crucial in further developing and refining guidelines.

Partnering to Harmonize IRBs for Community-Engaged Research to Reduce Health Disparities

Emerging advances in health disparities research include controlled trials and comparative effectiveness studies that are frequently conducted at multiple community and academic sites. Review by different institutional review boards (IRBs) presents a major impediment to the timely and effective conduct of such research. When research involves minority and underserved communities as well as multiple geographic regions, institutional requirements and interpretation of ethical standards may vary substantially. Such variations can complicate the informed consent process and research protocol, and may undermine participant respect and trial quality. In addition, multiple IRB review can lead to unnecessary delays, jeopardizing funding and capacity to perform collaborative projects. In response to these issues, the Research Centers in Minority Institutions (RCMI) Translational Research Network (RTRN) is developing a community-partnered approach to streamlining IRB review across its consortium of 18 RCMI grantee institutions that will ensure compliance while enhancing the quality of health disparities research.

Lysosomal storage diseases: Diagnostic confirmation and management of presymptomatic individuals

PurposeTo develop educational guidelines for the diagnostic confirmation and management of individuals identified by newborn screening, family-based testing after proband identification, or carrier testing in at-risk populations, and subsequent prenatal or postnatal testing of those who are presymptomatic for a lysosomal storage disease. MethodsReview of English language literature and discussions in a consensus development panel comprised an international group of experts in the clinical and laboratory diagnosis, treatment and management, newborn screening, and genetic aspects of lysosomal storage diseases. ResultsAlthough clinical trial and longitudinal data were used when available, the evidence in the literature is limited and consequently the recommendations must be considered as expert opinion. Guidelines were developed for Fabry, Gaucher, and Niemann-Pick A/B diseases, glycogen storage type II (Pompe disease), globoid cell leukodystrophy (Krabbe disease), metachromatic leukodystrophy, and mucopolysaccharidoses types I, II, and VI. ConclusionThese guidelines serve as an educational resource for confirmatory testing and subsequent clinical management of presymptomatic indivduals suspected to have a lysosomal storage disease; they also help to define a research agenda for longitudinal studies such as the American College of Medical Genetics/National Institutes of Health Newborn Screening Translational Research Network. Genet Med 2011:13(5):457– 484.

National Institute of Nursing Research Has Widened the Blue Highway of Translation Research

Congratulations the authors for clearly connecting the grand achievements and potential in science contemporary health research needs, specifically the need advance translational science. Woods and Magyary (2010) aptly underscore the quality improvement barriers created by restricted pathways between efficacy research and broad utilization of evidence improve clinical decision making. It was these narrow blue highways (Westfall, Mold, & Fagnan, 2007) that precipitated the National Institutes of Health (NIH) reinvent major portions of the health research enterprise in the 2004 NIH Roadmap, using Clinical and Translational Science Awards (CTSAs) as a key design. With this letter, I briefly describe activities that match the authors' recommendations and highlight recent activities already set in motion. Now only 7 years after the NIH Roadmap, nurse scientists are building a new infrastructure with significant funding from National Institute of Nursing Research (NINR)/NIH. This new structure is intended be our super highway as a national research network in translational science. This entity, the Improvement Science Research Network (ISRN, n.d.; Fohn, 2009), directly addresses Woods and Magyary's (2010) wise recommendation that magnify . . . efforts seek out and obtain funding support nursing's leadership and participation in collaborative endeavors through practice-based translational research networks that are interdisciplinary or primarily focused on nursing (p. 20). The ISRN proposal was a response NIH Request for Applications (RFA) Number RFA-OD-09-004, Recovery Act Limited Competition for NIH Grants: Research and Research Infrastructure Grand Opportunities (RC2). To the great benefit of nursing, the NINR was a participating organization, providing opportunity for nurses lead in collaborative, practice-based research. The RFA called for projects to support high impact ideas that lend themselves short-term funding, and may lay the foundation for new fields of investigation (NIH Grants Guide, 2009). With opportunity for large budgets (minimum of $1 million per year for 2 years), these were known as Grand Opportunity or GO grants. The NIH requested novel approaches in areas that addressed specific knowledge gaps, scientific opportunities, new technologies, data generation, or research methods that would benefit from an influx of funds quickly advance the area in significant ways. Applicants were requested propose either a specific research question or propose the creation of a unique infrastructure/resource designed accelerate scientific progress in the future (NIH Grants Guide, 2009). The ISRN proposed the latter. With the NIH/NINR funding, the ISRN has become a national research infrastructure that provides a test bed for the nascent field of improvement science (Fohn, 2009). Because of the very nature of health care improvement, the ISRN is interprofessional; because of the very nature of health care systems, it is decidedly focused. It offers a research coordinating center with a solid foundation in the decade-old Academic Center for Evidence-Based Practice (ACE). Key strategies include harnessing the energy created by the improvement and patient safety movements and capturing the motion created by the emphasis on clinical excellence such as the Magnet Recognition Program. The ISRN capitalizes on the core values of CTSAs, including community engagement through academic-practice partnership and commitment of moving knowledge through T1, T2, T3, and so forth. In addition, the ISRN honors the need for rigor in quality improvement testing (Berenholtz, Needham, Lubomski, Goeschel, & Pronovost, 2010) by applying scientific standards the evaluation of improvement strategies. To these ends, the ISRN has accomplished the following: (a) established stakeholder-based research priorities in improvement science, (b) coalesced almost 200 research associates, (c) created a forum for advancing capacity in improvement research methods (Improvement Science Summit), (d) launched three multisite improvement research studies, and (e) crafted a cyber environment for capacity building and conduct of multisite improvement research. …

Translational research network and patient registry for auto-inflammatory diseases

Auto-inflammatory diseases (AIDs) are characterized by recurrent self-limiting systemic inflammation. In a multicentre effort, we set out to register genetic, epidemiological and clinical features as well as prognostic factors of these diseases by prospective longitudinal and long-term documentation, in order to define novel AIDs and to better understand treatment responses and outcome. In 2009, a federally funded clinical and research consortium (AID-Net) was established, including an online registry for AIDs (http://www.aid-register.uk-essen.de). Inclusion criteria are disease-associated mutations for hereditary periodic fever syndromes [FMF, hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS), TNF receptor 1-associated periodic syndrome (TRAPS) and cryopyrin-associated periodic syndrome (CAPS)], or, alternatively, clinically confirmed AID, systemic-onset JIA (SoJIA) and periodic fever, aphthous stomatitis, pharyngitis and adenopathy (PFAPA) syndrome with unknown genetic background. Patients were recruited to the registry and patient material was deposited in biomaterial banks (DNA/serum). In addition, basic research projects were initiated that focus on molecular mechanisms of AID. During the first 9 months, 117 patients (65 males, 52 females; age 1-21 years) have been recorded and classified as FMF (n=84), HIDS (n=1), TRAPS (n=3) and CAPS (n=1); clinically confirmed AID (n=5); SoJIA (n=22); and PFAPA (n=1). One hundred and fifty blood samples of 18 patients were included in biomaterial banks. Recruitment and follow-up of patients with AID will enable us to comprehensively address the correlation between clinical and epidemiological data, genetics and biomarkers. The translational approach may help to identify genetic or inflammatory markers relevant for the course and outcome of diseases.

Abstract CN2-2: Development of therapeutic cancer vaccine and construction of clinical research network in Japan

Abstract cDNA microarray technologies have enabled us to obtain comprehensive data for gene expression profiles of human cancers. To isolate novel molecular targets for diagnosis and treatment of cancer, we constructed expression profile database of cancer cells originated from various organs with their corresponding non-cancerous tissues using a cDNA microarray that consists of more than 30,000 genes or ESTs. These experiments disclosed a number of genes that appeared to be involved in development and/or progression of cancers in those tissues. We also constructed expression profile database for 30 normal human tissues/organs. So far, we have analyzed approximately 1,400 clinical cancer samples of the liver, pancreas, stomach, colon, esophagus, bile duct, uterus, lung, ovary, kidney, urinary bladder, testis, prostate, breast, and soft tissues as well as acute and chronic myeloid leukemias. We have selected hundreds of candidate genes by the following criteria; (1) gene expressions were transactivated in a large proportion of cancer tissues in comparison with their corresponding normal tissues and (2) expression was not observed or hardly detectable in any of important vital organs. The further functional analysis of these molecules identified dozens of genes that are likely to function as oncogenes in various cancers. The suppression of expression of such genes with siRNA induced cell cycle arrest, apoptosis, or suppression of anchoring-dependent cell growth. We screened 9- or 10-amino-acid peptides corresponding to a part of such oncoantigens that induce cytotoxic T lymphocytes that would specifically kill cancer cells in an HLA-A restricted and antigen-dependent manner. We have already isolated nearly 60 peptides (HLA-A02 or HLA-A24 restricted) derived from about 50 oncoantigens and started translational research using some of them in August 2006. We have organized a group that performs translational research and now consists of ∼60 hospitals (Cancer Peptide Vaccine Translational Research Network = Captivation Network). We are now running more than 30 different protocols and more than 900 cancer patients have been enrolled by the end of 2009. The promising clinical data and immunological analysis of our translational research will be introduced in the meeting. These results indicated that systematic expression analysis should be a very effective approach for identification of molecules that are potential targets for development of novel therapeutic drugs. Citation Information: Clin Cancer Res 2010;16(7 Suppl):CN2-2

GPX – An Integrative Environment for the Storage and Retrieval of Raw and Processed Microarray Data

GPX is an environment for the storage and retrieval of raw and processed MIAME compliant microarray experiments. The system has been developed at the Scottish Centre for Genomic Technology and Informatics (GTI). GPX has a web accessible front end, GPX Discovery, that enables querying and retrieval of biochip data and experimental information based on various search criteria. GPX Discovery also enables the comparison of microarray platforms using the BioLink MatchMaker interface. GPX has been in use since 2003 to provide online access to raw, processed and meta microarray data analysing gene content, expression protein levels in the fields of immunity, oncology, infection and is part of the Edinburgh National Translational Cancer Research Network Centre resources. from BioSysBio: Bioinformatics and Systems Biology Conference Edinburgh, UK, 14–15 July 2005

Academic Clinical Oncology and Radiobiology Research Network (ACORRN): An NCRI Initiative to Address the Infrastructure and Capacity Deficit in Radiotherapy and Radiobiology Research in the UK

Radiotherapy remains the most commonly used anticancer treatment, and currently 50% of cancer patients in the UK are treated with radiotherapy at some point in their management. Radiotherapy is second only to surgery in its curative potential. Over the past 10 years, rapid technological advances have allowed more accurate radiotherapy delivery. We are also moving closer to being able to optimise patient treatment based on a rapidly evolving understanding of the genetics and biology of individuals and their tumours, and how these relate to prediction of treatment outcomes. The expectation of these advances over the coming years is that more patients will now be cured of their cancer, with a reduction in treatment-related side-effects. The current position in the UK, however, contrasts with much of the progress seen in cancer biology, with a sharp decline in the number of clinical academics and radiation biologists over the past 10 years. This has resulted in the radiotherapy and radiobiology communities having insufficient infrastructure or individuals to respond to the Department of Health need to develop and capitalise on these advances. To address the infrastructure and capacity deficit, the National Cancer Research Institute (NCRI), in response to a proposal from the research community, has established a UK network (ACORRN), aiming to develop an integrated UK radiotherapy and radiobiology

Show me the genes – I will tell you who/how to treat!

Show me the genes – I will tell you who/how to treat!